Cesiumiodide

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An aqueous extract (27.5 g) of Ircinia ramosa collected in Australia was fractionated on C4 reversed-phase media, Sephadex LH-20, and C18 HPLC (eluted with a 45-100% gradient of CH3CN in H2O with 0.1% TFA) to give chondropsin A (FIG. 1A, compound (1)) (1 mg) and 73-deoxychondropsin A (5 mg) (FIG. 1A, compound (4)). 73-deoxychondropsin A was obtained as a white powder; [α]D +2.0 (c 0.3, MeOH); W (MeOH) λmax (log ε) 216 (4.62), 226 (4.61), 261 (4.56) nm; IR υmax (film) 3500-3200, 1660, 1620, 1532, 1204, 1138, 998 cm−1; 1H and 13C NMR, see Table 5; HRFABMS (CsI-doped) obs. [M+Cs]+, m/z 1704.8308, C83H133CsN3O25 requires 1704.8279. HRFABMS established the molecular formula of (4) as C83H133N3O25, which only differed from (1) by a lack of one oxygen atom. The 1H and 13C NMR spectra of (4) (Table 5) were virtually superimposable with those of (1). The only significant spectral differences between the two compounds occurred in a region centered around C-73. It was apparent that the oxymethine at C-73 in (1) was replaced with a methylene in (4). HMBC correlations observed from H-53 (δ 5.42) and NH-57 (δ 7.62) to C-55 (δ 78.2) confirmed the presence of a C-55 oxymethine group in (4), while an HMBC correlation from H-55 (δ 3.36) to C-73 (δ 40.3) established the position of the new methylene group. A DEPT experiment confirmed that the carbon at δ 40.3 had two attached protons and COSY correlations from H-56 (δ 4.07) to the heavily overlapped region of the H2-73 protons (δ 1.46 and 1.54) were consistent with the presence of a methylene at C-73. Treatment of (4) with diazomethane provided a bis methyl ester derivative (MNa+, m/z 1622.9) (FIG. 1A, compound (5)) and data from a comprehensive set of 2-D NMR experiments with (4) verified that the only difference between (1) and (4) was at C-73.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 6-hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline (25 g, 15.3 mmol), CsI (4 g, 15.3 mmol) and bromoacetaldehyde dimethyl acetal (40 ml, 338 mmol) in DMF (600 ml) is added Cs2CO3 (137.5 g, 460 mmol). The reaction mixture is heated at 60° overnight. After this time, the reaction is poured into 1 liter brine and the resulting suspension is extracted with EtOAc (4×400 ml). The combined EtOAc extracts are dried over MgSO4 and concentrated in vacuo. The residue is washed with Et2O to yield 6-(2,2-dimethoxyethoxy)-1-oxo-1,2,3,4-tetrahydroisoquinoline as a crystalline solid. The reaction mixture is heated at 60° overnight the resulting suspension is extracted with EtOAc (4×400 ml) The combined EtOAc extracts are dried over MgSO4 concentrated in vacuo The residue is washed with Et2O

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 6-hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline (25 g, 15.3 mmol), CsI (4 g, 15.3 mmol) and bromoacetaldehyde dimethyl acetal (40 ml, 338 mmol) in DMF (600 ml) is added Cs2CO3 (137.5 g, 460 mmol). The reaction mixture is heated at 60° overnight. After this time, the reaction is poured into 1 liter brine and the resulting suspension is extracted with EtOAc (4×400 ml). The combined EtOAc extracts are dried over MgSO4 and concentrated in vacuo. The residue is washed with Et2O to yield 6-(2,2-dimethoxyethoxy)-1-oxo-1,2,3,4-tetrahydroisoquinoline as a crystalline solid. The reaction mixture is heated at 60° overnight the resulting suspension is extracted with EtOAc (4×400 ml) The combined EtOAc extracts are dried over MgSO4 concentrated in vacuo The residue is washed with Et2O

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6-Hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline is treated with bromacetaldehyde dimethyl acetal, in the presence of Cs2CO3 and CsI in DMF to yield 6-(2,2-dimethoxyethoxy)-1-oxo-1,2,3,4-tetrahydroisoquinoline. Treatment with 2-chloromethylpyridine hydrochloride in the presence of sodium hydride in DMF yields 6-(2,2-dimethoxyethoxy)2-(2-pyridylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline. Hydrolysis with 20% aqueous sulfuric acid in THF yields α-[2-(2-pyridylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yloxy]-acetaldehyde which is then converted to 2-(2-pyridylmethyl)-6-[2-(N-hydroxyamino)-ethoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6-Hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline is treated with bromacetaldehyde dimethyl acetal, in the presence of Cs2CO3 and CsI in DMF to yield 6-(2,2-dimethoxyethoxy)-1-oxo-1,2,3,4-tetrahydroisoquinoline. Treatment with 2-chloromethylpyridine hydrochloride in the presence of sodium hydride in DMF yields 6-(2,2-dimethoxyethoxy)2-(2-pyridylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline. Hydrolysis with 20% aqueous sulfuric acid in THF yields α-[2-(2-pyridylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yloxy]-acetaldehyde which is then converted to 2-(2-pyridylmethyl)-6-[2-(N-hydroxyamino)-ethoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 174 mg (0.83 mmol) of N-[(6-chloropyridin-3-yl)methyl]-N′-cyanoethanimidamide are stirred into 5 ml of acetonitrile, and 543 mg (1.67 mmol) of cesium carbonate, 166 mg (0.88 mmol) of 3-bromo-1,1-dichloroprop-1-ene and 22 mg (0.08 mmol) of cesium iodide are added successively. The reaction mixture is then stirred at room temperature for 1 hour. The reaction mixture is concentrated under reduced pressure and then taken up in ethyl acetate, washed successively with 1 N aqueous hydrochloric acid, 1 N aqueous sodium hydroxide solution and saturated sodium chloride solution and dried over sodium sulphate. Concentration of the organic phase under reduced pressure and purification of the residue by column chromatography on silica gel using the mobile phase mixture ethyl acetate:cyclohexane (2:1) gives 215 mg (77% of theory) of N-[(6-chloropyridin-3-yl)methyl]-N′-cyano-N-(3,3-dichloroprop-2-en-1-yl)ethanimidamide are added successively The reaction mixture is concentrated under reduced pressure washed successively with 1 N aqueous hydrochloric acid, 1 N aqueous sodium hydroxide solution and saturated sodium chloride solution dried over sodium sulphate Concentration of the organic phase under reduced pressure and purification of the residue by column chromatography on silica gel using the mobile phase mixture ethyl acetate:cyclohexane (2:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 7-Nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine; compound with nitric acid (763 mg, 2.99 mmol) was suspended in acetonitrile (50.0 mL, 957 mmol) and 2-chloro-N,N-dimethyl-acetamide (400 mg, 3.29 mmol) was added. Cesium carbonate (2.44 g, 7.48 mmol) and cesium iodide (77.7 mg, 0.299 mmol) were added and the reaction was heated at reflux for 3 hours. The reaction was cooled to room temperature and then diluted with DCM (50 mL) and washed with water (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-15% MeOH/DCM as the eluting solvent to obtain N,N-Dimethyl-2-(7-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-acetamide as an orange solid (778 mg, 94%). m.p.=94-96° C.; LCMS (m/e) 278 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.02-7.97 (m, 2H), 7.25 (d, 1H, J=7.9 Hz), 3.34 (s, 2H), 3.12 (s, 3H), 3.08-3.02 (m, 4H), 2.99 (s, 3H), 2.80-2.73 (m, 4H). the reaction was heated at reflux for 3 hours washed with water (50 mL) The organic layer was dried over sodium sulfate filtered concentrated under reduced pressure Purification by silica gel chromatography

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Cesium iodide (1.29 g, 4.97 mmol), iodine (0.63 g, 2.48 mmol), copper iodide (0.283 g, 1.48 mmol) and amyl nitrite (0.87 g, 7.45 mmol) were added under argon to a solution of 2-(2-amino-pyrimidin-4-yl)-1-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]-pyridine-5-carboxylic acid tert-butyl ester (synthesised as reported in Example 9) (1.137 g, 3.30 mmol) in DME (30.0 ml). The reaction mixture was stirred at 80° C. for 4 h. DCM was added to the solution (20 ml) and the organic layer was washed with a saturated solution of NaHCO3 (1×30 ml), with a saturated solution of Na2S2O3 (1×30 ml), with purite water (1×30 ml) and it was dried over Na2SO4. The filtrate was purified by flash chromatography, over silica gel, using DCM/MeOH (9.8:0.2) as eluent, to afford 2-(2-iodo-pyrimidin-4-yl)-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (0.240 g, 0.53 mmol, 16%) as a yellow solid. the organic layer was washed with a saturated solution of NaHCO3 (1×30 ml), with a saturated solution of Na2S2O3 (1×30 ml), with purite water (1×30 ml) and it was dried over Na2SO4 The filtrate was purified by flash chromatography, over silica gel

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Cesium iodide (1.29 g, 4.97 mmol), iodine (0.63 g, 2.48 mmol), copper iodide (0.283 g, 1.48 mmol) and amyl nitrite (0.87 g, 7.45 mmol) were added under argon to a solution of 2-(2-amino-pyrimidin-4-yl)-1-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]-pyridine-5-carboxylic acid tert-butyl ester (synthesised as reported in Example 9) (1.137 g, 3.30 mmol) in DME (30.0 ml). The reaction mixture was stirred at 80° C. for 4 h. DCM was added to the solution (20 ml) and the organic layer was washed with a saturated solution of NaHCO3 (1×30 ml), with a saturated solution of Na2S2O3 (1×30 ml), with purite water (1×30 ml) and it was dried over Na2SO4. The filtrate was purified by flash chromatography, over silica gel, using DCM/MeOH (9.8:0.2) as eluent, to afford 2-(2-iodo-pyrimidin-4-yl)-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (0.240 g, 0.53 mmol, 16%) as a yellow solid. the organic layer was washed with a saturated solution of NaHCO3 (1×30 ml), with a saturated solution of Na2S2O3 (1×30 ml), with purite water (1×30 ml) and it was dried over Na2SO4 The filtrate was purified by flash chromatography, over silica gel

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (Analogous to the procedure described in Heterocycles, 2001, 55, 461-464). To a solution of 4-amino-6-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one from step (a) above (0.76 g, 3.5 mmol) in 20 mL of DCM was added CsI (0.91 g, 3.5 mmol), I2 (0.44 g, 1.75 mmol), and CuI (0.2 g, 1.06 mmol). To the mixture was added isoamyl nitrite (2.8 mL, Aldrich) and the reaction mixture was heated at 60° C. with stirring for 3 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was diluted with EcOAc (60 mL). The solution was washed with 25% NH4OH (2×30 mL), 5% Na2S2O3 (20 mL) and brine, dried over MgSO4 and filtered. The filtrate was evaporated and the residue was purified by silica gel column chromatography, eluting with 30% EtOAc/hexane to give the title compound as a brown solid. MS (ESI, pos. ion) m/z: 329 (M+1) The reaction mixture was cooled to room temperature filtered the filtrate was diluted with EcOAc (60 mL) The solution was washed with 25% NH4OH (2×30 mL), 5% Na2S2O3 (20 mL) and brine dried over MgSO4 filtered The filtrate was evaporated the residue was purified by silica gel column chromatography eluting with 30% EtOAc/hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a well stirred and warm suspension of 8-amino-1-methyl-N-[(1S)-2-morpholin-4-yl-1-phenylethyl]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (3 g, 6.92 mmol) in dimethoxyethane (240 mL), maintained in an inert atmosphere of argon, cesium iodide (2.16 g, 8.3 mmol), bisublimated iodine (870 mg, 3.46 mmol), copper iodide (460 mg, 2.42 mmol) and isopentyl nitrite (1.71 mL, 1.5 g, 12.46 mmol) were added, in sequence. The reaction mixture was stirred vigorously at 65-70° C. for 18 hours. After cooling in an ice-water bath, the solid was filtered off and the filtrate was diluted with dichloromethane (100 mL), washed with 30% ammonium hydroxide (50 mL), sodium thiosulphate (100 mL), brine and dried over anhydrous Na2SO4. The crude was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol 95:59) and 1.48 g of the title compound was isolated (40% yield). warm were added, in sequence The reaction mixture was stirred vigorously at 65-70° C. for 18 hours After cooling in an ice-water bath the solid was filtered off the filtrate was diluted with dichloromethane (100 mL) washed with 30% ammonium hydroxide (50 mL), sodium thiosulphate (100 mL), brine dried over anhydrous Na2SO4 The crude was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol 95:59)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a well stirred and warm suspension of 8-amino-1-methyl-N-[(1S)-2-morpholin-4-yl-1-phenylethyl]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (3 g, 6.92 mmol) in dimethoxyethane (240 mL), maintained in an inert atmosphere of argon, cesium iodide (2.16 g, 8.3 mmol), bisublimated iodine (870 mg, 3.46 mmol), copper iodide (460 mg, 2.42 mmol) and isopentyl nitrite (1.71 mL, 1.5 g, 12.46 mmol) were added, in sequence. The reaction mixture was stirred vigorously at 65-70° C. for 18 hours. After cooling in an ice-water bath, the solid was filtered off and the filtrate was diluted with dichloromethane (100 mL), washed with 30% ammonium hydroxide (50 mL), sodium thiosulphate (100 mL), brine and dried over anhydrous Na2SO4. The crude was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol 95:59) and 1.48 g of the title compound was isolated (40% yield). warm were added, in sequence The reaction mixture was stirred vigorously at 65-70° C. for 18 hours After cooling in an ice-water bath the solid was filtered off the filtrate was diluted with dichloromethane (100 mL) washed with 30% ammonium hydroxide (50 mL), sodium thiosulphate (100 mL), brine dried over anhydrous Na2SO4 The crude was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol 95:59)